Increased risk of lung cancer, non-Hodgkin's lymphoma, and leukemia following Hodgkin's disease.

The risk of second cancers (SCs) was assessed in 744 patients with Hodgkin's disease (HD) admitted to The Netherlands Cancer Institute from 1966 to 1983. Sixty-nine SCs were observed one month or more after start of first treatment. These included 14 cases of lung cancer, nine cases of non-Hodgkin's lymphoma (NHL), 16 cases of leukemia, and six cases of the myelodysplastic syndrome (MDS). The median interval between the diagnosis of HD and that of second lung cancer, NHL, and leukemia was 8.1, 13.3, and 5.7 years, respectively. The overall relative risks (RR) (observed/expected [O/E] ratios) of developing lung cancer, NHL, and leukemia were 4.9 (95% confidence limit [CL], 2.7 to 8.2), 31.0 (95% CL, 14.2 to 58.9) and 45.7 (95% CL, 26.1 to 74.2), respectively. At 15 years the cumulative risk of developing an SC amounted to 20.6% +/- 2.9%. The 15-year estimates of lung cancer, NHL, and leukemia were 6.2% +/- 1.9%, 5.9% +/- 2.1% and 6.3% +/- 1.7%, respectively. Increased lung cancer risk following HD has not frequently been clearly demonstrated before; that we were able to demonstrate such risk may be due to the completeness of follow-up over long periods that could be achieved in this study. Excess lung cancer risk was only noted in treatment regimens with radiotherapy (RT); also, all lung cancers arose in irradiation fields. Excess risk of leukemia was only found in treatment regimens involving chemotherapy (CT). For NHL, combined modality treatment was shown to be the most important risk factor. Risk of lung cancer and NHL increased with time since diagnosis. A time-dependent covariate analysis (Cox model) performed on leukemia and MDS showed an increasing risk with intensity of CT, age (greater than 40 years), and a splenectomy.

Second cancer risk following Hodgkin's disease: a 20-year follow-up study.

PURPOSE: To determine risk factors for the development of second primary cancers during long-term follow-up of patients with Hodgkin's disease (HD). PATIENTS AND METHODS: We assessed the risk of second cancers (SCs) in 1939 HD patients, who were admitted to the Netherlands Cancer Institute (NKI; Amsterdam) or the Dr Daniel den Hoed Cancer Center (DDHK; Rotterdam) between 1966 and 1986. For 97% of the cohort, we obtained a medical status up to at least January 1989. The median follow-up duration of the patients was 9.2 years; for 17% of the patients, follow-up was longer than 15 years. For more than 98% of all second tumors, the diagnosis was confirmed through a pathology report. RESULTS: In all, 146 patients developed a SC, compared with 41.9 cases expected on the basis of incidence rates in the general population (relative risk [RR], 3.5; 95% confidence interval [CI], 2.9 to 4.1). The mean 20-year actuarial risk of all SCs was 20% (95% CI, 17% to 24%). Significantly increased RRs were observed for leukemia (RR, 34.7; 95% CI, 23.6 to 49.3), non-Hodgkin's lymphoma (NHL) (RR, 20.6; 95% CI, 13.1 to 30.9), lung cancer (RR, 3.7; 95% CI, 2.5 to 5.3), all gastrointestinal cancers combined (RR, 2.0; 95% CI, 1.2 to 3.1), all urogenital cancers combined (RR, 2.4; 95% CI, 1.4 to 3.7), melanoma (RR, 4.9; 95% CI, 1.6 to 11.3), and soft tissue sarcoma (RR, 8.8; 95% CI, 1.8 to 25.8). As compared with the general population, the cohort experienced an excess of 63 cancer cases per 10,000 person-years. Cox-model analysis indicated the following as significant risk factors for developing leukemia: first-year treatment with chemotherapy (CT), follow-up treatment with CT, age at diagnosis of HD greater than 40 years, splenectomy, and advanced stage. Patients treated with CT in the 1980s had a substantially lower risk of leukemia than patients treated in the 1970s (10-year actuarial risks of 2.1% and 6.4%, respectively; P = .07). Significant risk factors for NHL were older age, male sex, and combined modality treatment as compared with either modality alone. Risk of lung cancer was strongly related to radiotherapy (RT), while an additional role of CT could not be demonstrated. After more than 15 years of follow-up, women treated with mantle-field irradiation before age 20 years had a greater than forty-fold increased risk of breast cancer (P < .001). CONCLUSION: While the long-term consequences of HD treatment as administered in the 1960s and 1970s are still evolving, it is promising that patients who received the new treatment regimens introduced in the 1980s have a much lower leukemia risk than patients treated in earlier years. Beginning 10 years after initial RT, the follow-up program of women who received mantle-field irradiation before age 30 years should routinely include breast palpation and yearly mammography.

Long-term risk of second malignancy in survivors of Hodgkin's disease treated during adolescence or young adulthood.

PURPOSE: To quantify the long-term risk of second primary cancers (SCs) in patients diagnosed with Hodgkin's disease (HD) during adolescence or young adulthood. PATIENTS AND METHODS: The risk of SCs was assessed in 1,253 patients diagnosed with HD before the age of 40 years and treated in two Dutch cancer centers between 1966 and 1986. The median follow-up duration was 14.1 years. RESULTS: In all, 137 patients developed SCs, compared with 19.4 cases expected on the basis of incidence rates in the general population (relative risk [RR] = 7.0; 95% confidence interval, 5.9 to 8.3). The 25-year actuarial risk of SC overall was 27.7%. The RR of solid tumors increased greatly with younger age at the first treatment of HD, not only for breast cancer but also for all other solid tumors, with RRs of 4.9, 6.9, and 12.7 for patients first treated at ages 31 to 39 years, 21 to 30 years, and

Histologic classification and immunophenotyping of canine non-Hodgkin's lymphomas: unexpected high frequency of T cell lymphomas with B cell morphology.

Using three different classification schemes (Rappaport, the Working Formulation, and the Kiel classification), 116 canine malignant lymphomas were classified histologically. The number of lymphomas with a completely follicular growth pattern was low (14.9%). The majority of the lymphomas (50.8%) had a diffuse type of architecture, while 34.3% were diffuse with some nodularity. In the Rappaport scheme, 69.3% of the canine lymphomas were classified as histiocytic lymphomas, but these consisted of a group of tumors with different morphologic and immunologic cell types. The Working Formulation and the Kiel classification could be applied to differentiate the canine lymphomas cytomorphologically. In both the Working Formulation and the Kiel classification, only a minority of lymphomas (16.4 and 12.0%, respectively) were low-grade malignant lymphomas. Large cell or centroblastic lymphomas were the most frequently encountered in the Working Formulation or the Kiel classification, respectively. Immunophenotyping of 95 lymphomas was performed with the aid of a panel of monoclonal and polyclonal antibodies. The majority of the lymphomas were of B cell origin (58.9%) while three were classified as non-B/non-T cell lymphomas. Contrary to the distribution pattern of human non-Hodgkin's lymphoma (NHL) in western countries, there was a high percentage of T cell lymphomas (37.9%) in the canine. However, the phenotype could not be predicted by the morphologic characteristics alone.

DNA ploidy and cell kinetic characteristics in canine non-Hodgkin's lymphoma.

Malignant lymphoma in the dog is frequently postulated and used as a therapeutic model for non-Hodgkin's lymphoma (NHL) in humans. In this study DNA ploidy and the cell kinetic characteristics of canine malignant lymphoma were studied by flow cytometric (FCM) nuclear DNA measurements on fresh frozen tumor tissue from 94 dogs with NHL and on material from non-neoplastic lymph nodes from 20 dogs. The results were correlated with histomorphology, immunophenotype and survival. All non-neoplastic tissues were diploid, whereas of the 94 lymphomas 74 were diploid or near-diploid and 20 aneuploid. Of the aneuploid lymphomas, 1 contained a hypoploid cell population. DNA-indices of the aneuploid peaks ranged from 0.87 to 1.21 (mean 1.11). The mean S-phase fraction (8.2%, SD 4.8) was significantly lower in the non-neoplastic tissues than in the lymphomas (11.4%, SD 5.1). A linear correlation was observed between FCM S-phase fractions and bromodeoxyuridine (BrdU) labeling indices (r = 0.78; p < 0.001) determined in paraffin-embedded tissue sections from 18 dogs with NHL after in vivo BrdU labeling. DNA ploidy status did not correlate to the S-phase fraction. There were no differences in S-phase fraction and DNA ploidy between B cell and T cell lymphomas or between different histological classes using the Working Formulation. No correlation was found between S-phase fraction or DNA ploidy and survival in a series of 59 dogs treated with a combination chemotherapy protocol. It is concluded that the frequency of DNA aneuploidy in canine malignant lymphoma is similar to that in human NHL. In contrast to findings in human NHL, however, no relationship was found between DNA ploidy or cell kinetic features and histomorphology or prognosis.

Detection of malignant cells in cerebrospinal fluid using fluorescence in situ hybridization.

Cytologic examination of cerebrospinal fluid (CSF) is the diagnostic gold standard for leptomeningeal metastasis (LMM). However, this technique is only moderately sensitive when routine staining procedures are applied. The use of fluorescence in situ hybridization (FISH) to identify malignant cells may have an additional value in diagnosing LMM, since numerical chromosomal aberrations (NCA) can be detected at the single cell level. We tested the feasibility of FISH to detect tumor cells in CSF by analyzing 22 samples with proven LMM with a probe for chromosome 1 (1q12) to detect NCA in the cells. A control group consisted of samples from 10 patients with inflammatory neurologic disease. In 7 LMM samples no cells or only lysed cells were found, due to time delay before fixation. Of the other 15 LMM samples analyzed, 13 showed NCA (87%), while no NCA were found in the control group. Our results indicate that FISH may be a useful additional diagnostic tool to the cytodiagnosis of CSF in cases of LMM. We expect that FISH can become an additional marker for malignancy at the single cell level in patients with LMM, which may also be of use to determine the effect of therapy for LMM.

Intraventricular methotrexate therapy of leptomeningeal metastasis from breast carcinoma.

Treatment results of leptomeningeal metastasis are reported in 33 breast cancer patients. They were divided into three groups: group 1, 19 patients, received intraventricular methotrexate (MTX) with doses based on CSF MTX levels; group 2, 6 patients, received whole brain radiation followed by a course of MTX given by lumbar punctures; group 3, 8 patients, was not treated. Median survival in group 1 was 6 months; 25% survived 1 year or more. Median survival (1 to 2 months) in groups 2 and 3 was significantly shorter. Neurologic improvement was seen in an average time of 4 weeks in about 80% of group 1 patients. Two of group 2 patients improved at 3 weeks, and all group 3 patients deteriorated. Carcinomatosis caused death significantly less often in group 1 than in the other groups.

Polyethylene glycol-L-asparaginase versus native L-asparaginase in canine non-Hodgkin's lymphoma.

42 dogs with non-Hodgkin's lymphoma (NHL) were randomized for treatment with either PEG-L-asparaginase 10 IU/kg intramuscularly (n = 22) or L-asparaginase 400 IU/kg intraperitoneally (n = 20). Another 20 dogs were treated with either PEG-L-asparaginase 30 IU/kg (n = 10) or L-asparaginase 400 IU/kg (n = 10). Each treatment protocol consisted of two asparaginase treatments followed by a 10-week period of induction chemotherapy and then maintenance on asparaginase until progression occurred. No significant differences were found between treatments in the response rates after 2 weeks of asparaginase therapy or in the time to relapse, the time to treatment failure or the remission period. The reaction to asparaginase after the initial 2 weeks was a prognostic factor for the total duration of remission under asparaginase maintenance therapy. No side-effects were noted in the dogs treated with PEG-L-asparaginase, whereas 14 (48%) of the L-asparaginase treated dogs had side-effects related to this drug, including anaphylactic shock (9), anorexia or vomiting (4), hypersensitivity-related oedema (3), seizures (1) and acute pancreatitis (1). No abnormalities in clotting times, fibrinogen levels or antithrombin-III levels were found in any of the 62 dogs. PEG-L-asparaginase has the same anti-tumour activity as native L-asparaginase in dogs with NHL, but lacks side-effects.

Treatment results of primary stage I and II non-Hodgkin's lymphoma of the stomach.

Gastric lymphoma in stage I or II was usually treated by partial gastrectomy and total abdominal irradiation in our institute since 1970. Since 1978, a number of patients were also treated without laparotomy, in clinical stage I with radiotherapy only and in clinical stage II with combined modality treatment. Treatment results of 58 patients are reported. A relapse-free survival rate of 85% was reached for 24 patients treated with resection and irradiation either in stage I or II, and for seven patients in stage I who did not undergo surgery. For these patients, survival in stage I was 85%, in stage II, however, survival dropped to 60% due to intercurrent deaths. Seven stage II2 patients received intensive chemotherapy and radiotherapy with 58% relapse-free survival. Twenty patients could not be treated according to the outlined treatment protocol. For the total group, survival in stage I is 65% and in stage II 35%. In the Addendum, an additional group of 17 patients is mentioned with the same result.

Results of radiotherapy in patients with stage I orbital non-Hodgkin's lymphoma.

This paper describes the results of radiotherapy in early stage orbital non-Hodgkin's lymphoma. From 1970 to 1985, 33 orbital localizations in 30 patients were treated. The total dose applied ranged from 21 to 57 Gy (2 Gy per fraction), two-thirds of all patients received a dose of 40 Gy. The complete-response rate was 94% and the 10 years actuarial survival was 90%; no significant difference in survival was observed between patients with low grade or intermediate grade lymphoma. No local recurrence was detected during follow up and 20% of the patients developed generalized disease. Two optic nerve neuropathies and three retinopathies were observed in five patients, four of these occurred at a dose level of less than 43 Gy. Keratitis occurred in 58% of the patients treated, a sicca syndrome in 30% and cataract of different grades in 58% of the patients treated. Although local control was excellent, severe complications were observed in 13% of the patients who received a dose of less than 43 Gy.

Actinomycosis, a sheep in wolves' clothes.

We present a patient referred for radiotherapy for a presumed pulmonary malignancy, who was found to suffer from an actinomycotic infection. This case illustrates the importance of early consideration of actinomycosis when diagnostic methods are negative for malignancy or specific chestwall and bony lesions are observed.

Stage is a better prognostic indicator than morphologic subtype in primary noncutaneous T-cell lymphoma.

The authors reviewed 28 primary noncutaneous T-cell lymphomas, referred to the Comprehensive Cancer Center Amsterdam, using the updated Kiel classification. Clinical course was related with stage of disease, morphologic subtype, and immunophenotype of the tumor cells. The incidence of primary noncutaneous T-cell lymphomas was 4.1 cases per 1,000,000 people per year. Morphologic classification was difficult and arbitrary. Immunohistochemistry contributed considerably in diagnosis of this group of tumors. All primary noncutaneous T-cell lymphomas had a poor prognosis, with no significant difference between predominantly small cell (low-grade) and large cell (high-grade) tumors. The only parameter significantly correlating with survival was the stage of the disease at presentation. The results suggest that all types of primary noncutaneous T-cell lymphoma are to be considered high grade and that primary localization (cutaneous vs. noncutaneous) and stage of disease at presentation appear to be more important as predictors of clinical outcome than morphologic or immunophenotypic subtype.

Relation of CD30 expression to survival and morphology in large cell B cell lymphomas.

AIMS: To investigate whether CD30 expression is correlated with anaplastic morphology, and whether this correlated with a better survival in large cell B cell lymphomas, as has been described for T cell lymphomas. METHODS: CD30 expression was investigated using frozen sections in a series of 146 large cell B cell lymphomas. Clinical data and follow up information were collected from 25 lymphomas with strong CD30 expression, 30 lymphomas with partial CD30 expression, and a control group of 25 lymphomas which did not express CD30. RESULTS: Morphological distinction between anaplastic and non-anaplastic tumours was difficult. Of the cases with an anaplastic morphology, 50% were CD30 positive, as were 24% of the polymorphic centroblastic B cell lymphomas. Only 65% of the morphologically non-anaplastic tumours were completely CD30 negative. There was no difference in survival among patients with lymphomas expressing CD30 and those that did not. Patients with morphologically anaplastic B cell lymphomas did not differ in their survivals from those with other high grade B cell lymphomas. Clinical stage at presentation was the only variable that was significantly associated with survival. CONCLUSIONS: CD30 expression occurs frequently in large cell B cell lymphomas and is poorly related to anaplastic morphology. Morphological distinction between anaplastic and non-anaplastic tumours is difficult. In contrast to T cell lymphomas, CD30 positive B cell lymphomas do not show a relatively favourable clinical course. The results presented here raise serious doubts as to whether large cell B cell lymphoma, based on the expression of CD30 or anaplastic morphology, can really be termed a separate entity.

Lymphoid proliferations in the orbit: malignant or benign?

Clinical, pathological, and immunological analysis of 20 patients with ocular adnexal lymphoid disease has demonstrated several parameters which are useful for distinguishing malignant from benign lesions. Patients in the fourth or fifth decade of life presenting with an acute history of pain, oedema, epiphora, double vision, and ptosis, with a mass localised in the lacrimal gland area, are more likely to have a pseudolymphoma or a chronic inflammatory lesion than a true non-Hodgkin lymphoma (NHL). It is not possible to obtain a definite diagnosis without surgical intervention, because only three out of nine patients with orbital NHL had evidence of a monoclonal B cell population in peripheral blood on admission to the Orbital Centre. Furthermore it was confirmed that the identification of the various orbital lymphoid infiltrates becomes more distinct when immunological techniques are added to the clinical and histopathological methods of investigation. Multidisciplinary cooperation leads to further improvement of diagnosis and treatment of ocular adnexal lymphoproliferative disease.

Therapy-relevant discrepancies between diagnoses of institutional pathologists and experienced hematopathologists in the diagnosis of malignant lymphoma.

We have studied therapy-relevant discrepancies in the diagnoses of institutional pathologists and a panel of 4 experienced hematopathologists in 375 cases from patients with malignant lymphoma. Two hundred and fifty four cases (68%) were contributed by non-panel pathologists and 121 (32%) by individual panel pathologists. Overall, in 24% (91/375) of the cases, therapy-relevant discrepancies were present between institutional pathologists and panel diagnoses. Thirty-four percent (87/254) therapy-relevant discrepancies were present in cases contributed by non-panel pathologists, whereas in only 3% (4/121) discrepancies were found in cases forwarded by individual panel pathologists. The percentages erroneously diagnosed Hodgkin's disease by non-panel pathologists and individual panel pathologists were 8 and 0% respectively and faulty diagnosed Non-Hodgkin lymphomas 5 and 0%, whereas the number of consultation cases, in which the referring pathologist was not certain of his diagnosis, appeared to be 24 and 3% for non-panel and panel pathologists respectively. In addition, in 14% of panel confirmed NHL contributed by non-panel pathologists, therapy-relevant discrepancies in the degree of malignancy grading according to the Working Formulation were present, whereas no discrepancies in malignancy grading were noted between individual panel members and panel diagnoses. Apart from extensive hematopathological experience, a reason for the higher diagnostic accuracy of the panel pathologists could well be the frequency in which the diagnoses were supplemented by immunophenotyping: in 22% of the cases from non-panel pathologists and 63% of the cases from panel pathologists immunophenotyping on frozen sections was carried out.(ABSTRACT TRUNCATED AT 250 WORDS)

Atypia in fine-needle aspiration cytology of the breast: a histologic follow-up study of 301 cases.

A gray area of uncertainty exists in fine-needle aspiration (FNA) cytology of the breast in which common criteria to distinguish benign from malignant lesions overlap. Aims of this study were to define this area and to evaluate statistically cytomorphologic criteria in a semiquantitative analysis. In a test set of specimens from well-differentiated carcinomas and benign proliferative lesions, signs of malignancy were cell dissociation, arrangement in small clusters, nuclei greater than 16 microns, anisonucleosis, irregular nuclear borders, nucleoli, and necrosis. Features in favor of benignancy were large monolayers, nuclei less than 16 microns without variation in size, smooth nuclear borders, and bipolar nuclei in the monolayers. Originally the term "atypia" had been applied to 956 (12%) of all FNAs of the breast performed at our institute from 1974 to 1985. Using these criteria in a review of all 301 cases in which histologic follow-up and cellular smears were available, much better results were obtained than originally; specificity increased from 80% to 95%, and sensitivity increased from 60% to 90%. The number of overdiagnoses decreased from 24 to seven, and underdiagnoses decreased from 57 to nine. In this selected series, the area of uncertainty was restricted to 16% of the cases; the number of these cases that proved to be malignant and benign was equal. In such cases of indistinct cytomorphologic criteria, a surgical biopsy is indicated for histologic studies.

Fine needle aspiration cytology of radiation-induced changes in nonneoplastic breast lesions. Possible pitfalls in cytodiagnosis.

The range of radiation-induced changes in fine needle aspiration (FNA) smears of the breast is described. In 41 of more than 800 patients who underwent breast-conserving treatment, a palpable breast lesion developed, and FNA was performed. In six cases, a recurrent carcinoma was present. In the remaining cases, three patterns of nonneoplastic lesions could be discerned: epithelial atypia (14 cases), fat necrosis (10 cases) and poorly cellular smears without epithelial atypia or fat necrosis (13 cases). It is important to be familiar with the patterns of radiation-induced epithelial atypia, since such atypia may lead to a misdiagnosis of recurrent carcinoma. These atypical cells may show impressive anisocytosis and anisonucleosis; however, the nuclear/cytoplasmic ratio remains normal and an admixture of bipolar cells is present. Cell dissociation and necrotic cell debris, as often seen in breast cancer smears, were never encountered in FNA smears from radiated nonneoplastic breasts.

Fine needle aspiration biopsy diagnosis of rhabdomyosarcoma. An immunocytochemical study.

Specific antibodies against desmin, skeletal muscle actin and myosin were assessed for their usefulness in the cytodiagnosis of five rhabdomyosarcomas: one well-differentiated, two moderately differentiated and two poorly differentiated lesions. Acetone-fixed smears from fine needle aspiration biopsies and the avidin-biotinyl-peroxidase complex technique were used. All aspirates were positively immunostained with antibodies against desmin and actin. Myosin could only be detected in the moderately and well-differentiated tumors. The percentage of tumor cells positive for any of the three proteins was positively correlated with the overall degree of differentiation. However, the number of positive tumor cells decreased in the sequence desmin-actin-myosin. The results indicate the value of antibodies, especially those against skeletal muscle actin, in aiding in the cytodiagnosis of rhabdomyosarcoma, particularly with respect to its differential diagnosis from small round cell tumors in children and pleomorphic sarcomas in adults.

Sarcoma arising from interdigitating cells. Cytology and cytochemistry.

The cytologic features of a highly malignant sarcomatous tumor in a 37-year-old male, arising from interdigitating cells and localized in the mediastinum, lymph nodes and skin, are described. Cytologically this sarcoma was characterized by large cells with ill-defined, faintly basophilic cytoplasm, monocytoid or multilobulated nuclei and a reticular chromatin structure; very prominent nucleoli were seen in some of the cells. Some of the tumor cells were spindle shaped. The ultrastructurally characteristic invaginations of the cell membrane were not obvious in the cytologic smear, although the nuclear membrane showed deep, narrow, channel-like indentations. The specific ultrastructural, immunologic and cytochemical characteristics of the interdigitating cells were recognized in the tumor cells. Adenosine triphosphatase was present in the tumor cells in large amounts, while acid phosphatase, acid alpha-naphthyl acetate esterase and other enzymes were absent. The described tumor must be considered another tumor of the mononuclear phagocyte system; the proposed name is "interdigitating-cell sarcoma."

Prognostic factors for treatment of malignant lymphoma in dogs.

Pretreatment characteristics of 138 dogs with malignant lymphoma were analyzed to determine prognostic factors associated with outcome (ie, complete response rate, time to relapse after complete response, survival time). Dogs were all treated for 10 weeks, using a standard induction chemotherapy protocol, and were then given asparaginase weekly. Once the disease became progressive, second-line chemotherapy was instituted. Age, sex, weight, clinical stage, performance grade, immunophenotype, and malignancy grade assigned according to the National Cancer Institute's Working Formulation were not associated with complete response rate. However, malignancy grade assigned according to the Kiel classification was found to be associated with complete response rate; dogs with high-grade malignancies had a significantly higher complete response rate than did dogs with low-grade malignancies. By means of multivariate analysis, clinical stage and immunophenotype were found to be prognostic factors for time to relapse (among dogs that had had a complete response) and survival time. In addition, malignancy grade assigned according to the Kiel classification was found to be a prognostic factor for time to relapse; whereas, malignancy grade assigned according to the Working Formulation was determined to be a prognostic factor for survival time.